WO1993023380A1 - Derives aza-bicycliques en pont utiles comme antagonistes de la substance p - Google Patents

Derives aza-bicycliques en pont utiles comme antagonistes de la substance p Download PDF

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Publication number
WO1993023380A1
WO1993023380A1 PCT/US1993/001429 US9301429W WO9323380A1 WO 1993023380 A1 WO1993023380 A1 WO 1993023380A1 US 9301429 W US9301429 W US 9301429W WO 9323380 A1 WO9323380 A1 WO 9323380A1
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Prior art keywords
alkyl
phenyl
optionally
alkylamino
benzhydryl
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PCT/US1993/001429
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English (en)
Inventor
Manoj C. Desai
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Pfizer Inc.
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Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to DE69331190T priority Critical patent/DE69331190T2/de
Priority to US08/335,726 priority patent/US5498614A/en
Priority to EP93906038A priority patent/EP0641328B1/fr
Priority to AT93906038T priority patent/ATE209186T1/de
Priority to DK93906038T priority patent/DK0641328T3/da
Publication of WO1993023380A1 publication Critical patent/WO1993023380A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to novel bridged aza-bicyclic derivatives as Substance receptor and related compounds, pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment and prevention of inflammatory and central nervous system disorders, as well as several other disorders.
  • the pharmaceutically active compounds of this invention are substance receptor.
  • This invention also relates to novel intermediates used in the synthesis of such substance receptor.
  • Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being named because of their prompt stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmacologically active neuropeptide that is produced in mammals (having originally been isolated from gut) and possesses a characteristic amino acid sequence that is illustrated by D. F. Veber et al. in U.S. Patent No. 4,680,283. The wide involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For instance, substance P has recently been shown to be involved in the transmission of pain or migraine (see B.E.B.
  • Piperidine derivatives and related heterocyclic nitrogen containing compounds that are useful as substance receptor are referred to in United States Patent Application Serial No. 590,423 filed September 28, 1990, United states Patent Application Serial No. 717,943 filed on June 20, 1991, and United States Patent Application Serial No. 724,268 filed July 1, 1991.
  • Non-peptidic antagonists have also been described in published European patent application 0436334.
  • the present invention relates to compounds of the formula
  • m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH 2 ) m may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH 2 ) m may optionally be substituted with R 8 ;
  • w is an integer from 0 to 2;
  • y is an integer from 1 to 4.
  • z is an integer from 1 to 4, and wherein any one of the carbon atoms of said (CH 2 ) z may optionally be substituted with
  • R 1 is hydrogen or (C 1 -C 8 ) alkyl optionally substituted with hydroxy, alkoxy or fluoro;
  • R 2 is a group selected from hydrogen, (C 1 -C 6 ) straight or branched alkyl, (C 3 -C 7 )cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C 2 -C 6 ) alkyl, benzhydryl and benzyl, wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl
  • R 5 is hydrogen, phenyl or (C 1 -C 6 ) alkyl
  • R 2 and R 5 together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;
  • R 3 is aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; or cycloalkyl having 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C 3 -C 7 ) cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 6 )alkoxy optionally substituted with from one to three fluorine
  • R 6 is NHCH 2 R 9 , NHSO 2 R 9 or one of the groups set forth in any of the definitions of R 2 and R 4 ;
  • R 9 is (C 1 -C 6 ) alkyl, hydrogen, phenyl or phenyl (C 1 - C 6 ) alkyl;
  • Preferred compounds of formula I are those wherein m, w, y, z, R 3 , R 4 , R 5 , R 6 , and R 8 are defined as above and R 2 is a radical selected from phenyl, naphthyl and benzhydryl; wherein each of said phenyl, naphthyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, amino, (C 1 -C 6 ) -alkylamino,
  • phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl.
  • the present invention also relates to compounds of formula I wherein m, w, y, z, R 3 , R 5 , R 6 and R 8 are defined as above; and
  • R 2 is a group selected from hydrogen, phenyl, naphthyl and benzhydryl; wherein each of said phenyl, naphthyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, trifluoromethyl, amino,
  • a preferred compound of the formula I is (3RS,4RS)-3- phenyl-4-(2-methoxybenzyl)amino-2-azabicyclo-[3.3.1]nonane.
  • the present invention also relates to compounds of the formula
  • a preferred compound of formula IV is (3RS, 4RS)-2- (benzyloxycarbonyl) -3-phenyl-4-amino-2-azabicyclo[3.3.1]nonane.
  • the present invention also relates to compounds of the formula wherein w, y, z, R 2 , R 4 , and R 5 are defined as above.
  • the compounds of formula V are novel intermediates used in the synthesis of compounds of formula I.
  • a preferred compound of formula V is (3RS, 4RS)-2-(benzyloxycarbonyl)-3-phenyl-4-carboxamide-2-azabicyclo[3.3.1]nonane.
  • the present invention also relates to compounds of the formula
  • R 7 is selected from the group H, alkyl (C 1 -C 6 ) branched or unbranched.
  • the compounds of formula VI are novel intermediates used in the synthesis of compounds of formula I.
  • a preferred compound of formula VI is (3RS, 4RS)-2-(benzyloxycarbonyl)-3-phenyl-2-azabicyclo-[3.3.1]nonane-4-carboxylic acid, methyl ester.
  • the present invention also relates to compounds of the formula
  • the present invention also relates to compounds of the formula
  • halo as used herein, unless otherwise indicated, includes chloro, fluoro, bromo and iodo.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched or cyclic moieties or combinations thereof.
  • one or more substituents includes from one to the maximum number of substituents possible based on the number of available bonding sites.
  • Formula I above includes compounds identical to those depicted but for the fact that one or more hydrogen atoms are replaced by radioactive isotopes thereof.
  • Such radiolabelled compounds are useful as research and diagnostic tools in metabolism pharmokinetic studies and in binding assays. Specific applications in research include radioligand binding assays, autoradiography studies and in vivo binding studies, while specific applications in the diagnostic area include studies of the substance P receptor in the human brain and in vivo binding in the relevant tissues for inflammation, e.g., immune-type cells or cells that are directly involved in inflammatory bowel disorders and the like.
  • the present invention also relates to a pharmaceutical composition for treating or preventing a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), reflux gastroesophogal disease, hypertension, anxiety, depression or dysthymic disorders, colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina, migraine and Reynaud's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimer's disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus erythemato
  • the present invention also relates to a method of treating or preventing a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), reflux gastroesophogal disease, hypertension, anxiety, depression or dysthymic disorders, colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina, migraine and Reynaud's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimer's disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus erythematos
  • the present invention also relates to a pharmaceutical composition for antagonizing the effects of substance P in a mammal, including a human, comprising a substance P antagonizing amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also relates to a method of antagonizing the effects of substance P in a mammal, including a human, comprising administering to said mammal a substance P antagonizing amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a pharmaceutical composition for treating or preventing a disorder in a mammal, including a human, resulting from an excess of substance P, comprising a substance P antagonizing amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also relates to a method of treating or preventing a disorder in a mammal, including a human, resulting from an excess of substance P, comprising administering to said mammal a substance P antagonizing amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a pharmaceutical composition for treating or preventing a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), reflux gastroesophogal disease, hypertension, anxiety, depression or dysthymic disorders, colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina, migraine and Reynaud's disease, fibrosing and collagen diseases such as scleroderma.
  • inflammatory diseases e.g., arthritis, psoriasis, asthma and inflammatory bowel disease
  • reflux gastroesophogal disease e.g., hypertension, anxiety, depression or dysthymic disorders, colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity
  • eosinophilic fascioliasis reflex sympathetic dystrophy such as shoulder/hand syndrome
  • addiction disorders such as alcoholism
  • stress related somatic disorders peripheral neuropathy, neuralgia
  • neuropathological disorders such as Alzheimer's disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis
  • disorders related to immune enhancement or suppression such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis in a mammal, including a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in antagonizing the effect of substance P at its receptor site, and a pharmaceutically acceptable carrier.
  • the present invention also relates to a method of treating or preventing a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), reflux gastroesophogal disease, hypertension, anxiety, depression or dysthymic disorders, colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina, migraine and Reynaud's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimer's disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus erythematos
  • the present invention also relates to a pharmaceutical composition for treating or preventing a disorder in a mammal, including a human, the treatment or prevention of which is effected or facilitated by a decrease in substance P mediated neurotransmission, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in antagonizing the effect of substance P at its receptor site, and a pharmaceutically acceptable carrier.
  • the present invention also relates to a method of treating or preventing a disorder in mammal, including a human, the treatment or prevention of which is effected or facilitated by a decrease in substance P mediated neurotransmission, comprising administering to said mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in antagonizing the effect of substance P at its receptor site.
  • the present invention also relates to a pharmaceutical composition for treating or preventing a disorder in a mammal, including a human, the treatment or prevention of which is effected or facilitated by a decrease in substance P mediated neurotransmission, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such disorder, and a pharmaceutically acceptable carrier.
  • the present invention also relates to a method of treating or preventing a disorder in mammal, including a human, the treatment or prevention of which is effected or facilitated by a decrease in substance P mediated neurotransmission, comprising administering to said mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such disorder.
  • the compounds of the formula I have chiral centers and therefore exist in different enantiomeric and diasteriomeric forms.
  • This invention relates to all optical isomers and all stereoisomers of compounds of the formula I, and mixtures thereof.
  • Formula I above includes compounds identical to those depicted but for the fact that one or more hydrogen or carbon atoms are replaced by radioactive isotopes thereof.
  • Such radiolabelled compounds are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays. Specific applications in research include radioligand binding assays, autoradiography studies and in vivo binding studies, while specific applications in the diagnostic area include studies of the substance P receptor in the human brain in in vivo binding in the relevant tissues for inflammation, e.g. immune-type cells or cells that are directly involved in inflammatory bowel disorders and the like. Included among the radiolabelled forms of compounds of the formula I are the tritium and C 14 isotopes thereof.
  • the compounds of the formula I may be prepared as described in the following reaction scheme and discussion.
  • Scheme 1 illustrates a method of preparing compounds of the formula I. Referring to scheme 1, a compound of the formula XII is reacted with a compound having the formula
  • This reaction is generally carried out by adding the compound of formula XII in tetrahydrofuran to lithium diisopropylamide monotetrahydrofuran at a temperature from about -78°C to about -50°C, stirring the resulting mixture for about 0.25 to about 10 hours, and then adding the compound of formula XI to the mixture at approximately the same temperature over a period of about 5 minutes to about 1 hour.
  • This reaction produces a ⁇ -lactam of the formula X.
  • a compound of the formula X is reacted with a nitrogen-protecting reagent such as t-butyldimethylsilyl chloride (TBDMS-Cl), t-butyldimethylsilyl triflate (TBDMS-OTf) or benzyl bromide/t-butoxide, preferably TBDMS-Cl, to form a compound of the formula IX.
  • a nitrogen-protecting reagent such as t-butyldimethylsilyl chloride (TBDMS-Cl), t-butyldimethylsilyl triflate (TBDMS-OTf) or benzyl bromide/t-butoxide, preferably TBDMS-Cl
  • TBDMS-Cl benzyl bromide/t-butoxide
  • This reaction is typically carried out in a polar solvent such as DMF or triethylamine, preferably triethylamine, at a temperature of from about 0 to about 140°C
  • the hydrogen at carbon 3 of the cis amide protected lactam of formula IX then is stereochemically inverted by addition of a strong base and quenching the anion with a proton source, preferably acetic acid, to form the 2,3 trans isomer of the amide protected lactam.
  • This isomerization converts the cis lactam to the thermodynamically more stable trans form of formula VIII.
  • the solvent should be inert and solvent polarity can vary in a broad range. Examples of appropriate solvents are tetrahydrofuran, hexane and toluene.
  • the ⁇ lactam of formula VIII is converted into the compound of formula VII by simultaneous removal of the TBDMS group and cleavage of the ⁇ -lactam.
  • This process is typically conducted using a concentrated acid such as concentrated sulfuric or perchloric acid, preferably sulfuric acid, in a polar solvent such as a lower alcohol, preferably methanol, for about 0.5 to about 16 hours.
  • a concentrated acid such as concentrated sulfuric or perchloric acid, preferably sulfuric acid
  • a polar solvent such as a lower alcohol, preferably methanol
  • Suitable reaction temperatures range from about room temperature to about 150°C, with the reflux temperature of the solvent being preferred.
  • the product of this reaction is a compound having a structure similar to that of formula VII, except that the N-carbobenzyloxy group is replaced by hydrogen.
  • Treatment of this compound with benzylchloro-formate to produce a compound of the formula VII having the same stereochemistry is generally carried out in a polar solvent such as water, water/acetone, chloroform, dichloroethane or ethyl acetate in the presence of a base.
  • bases such as triethylamine, sodium bicarbonate and potassium bicarbonate.
  • This reaction may be conducted at temperatures from about 0°C to about 100°C, for a period of about 5 minutes to about 18 hours. Preferably, it is conducted at about 25°C.
  • the compound of formula VII may be cyclized to form the corresponding compound having the formula VI and the same stereochemistry with respect to the carbons to which R 2 , R 5 and COOR 7 are attached, by first reacting it with mercuric trifluoroacetate, mercuric chloride or mercuric acetate, and then reacting the product of such reaction with sodium borohydride, lithium triacetoxyborohydride or a similar reducing agent.
  • the reaction with the mercury salt is usually conducted in a polar solvent at a temperature from about -78°C to about 25°C. Suitable solvents include tetrahydrofuran, acetonitrile and nitromethane.
  • Reduction is carried out preferably using sodium borohydride in tetrahydrofuran at about 25°C.
  • Reduction with sodium borohydride is generally carried out by adding an aqueous solution of sodium borohydride to the reaction mixture from the foregoing reaction at a temperature from about -78°C to about 0°C, preferably at about 0°C.
  • reaction temperatures may range from about room temperature to about 100°C, with about 50°C being preferred.
  • the conversion of the carboxamide group of the compound of formula V to form a compound of the formula IV having the same stereochemistry may be accomplished by a Hoffmann degradation using reagents such as bromine/sodium methoxide in methanol, lead tetraacetate in t-butyl alcohol, tin (IV) chloride, iodobenzene bis(trifluoroacetate) in aqueous acetonitrile, sodium bromide or benzyltrimethyl ammonium tribromide.
  • the compound of formula V is treated with lead tetraacetate in t-butanol.
  • This reaction is typically carried out at a temperature from about room temperature to the reflux temperature of the solvent, preferably at the reflux temperature, for about 15 minutes to about 10 hours, preferably for about 3 to about 5 hours.
  • Reaction of the compound of formula V with an acid such as hydrochloric acid, trifluoroacetic acid or perchloric acid yields a compound of the formula having the same stereochemistry.
  • the solvent is typically a solvent such as methylene chloride, dioxane, ether or tetrahydrofuran, preferably dioxane.
  • This reaction is typically carried out at a temperature from about -10 to about 50°C, preferably at about 25°C, for about 0.5 to 24 hours.
  • Reductive amination of a compound of the formula R 3 CHO in the presence of a compound of the formula IV from the above step yields a compound of the formula III having the same stereochemistry.
  • reducing agents that may be used are hydrogen in the presence of a metal catalyst, sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride.
  • This reaction is generally carried out in a polar solvent such as acetic acid or a lower alkanol, in the presence of a dehydrating agent such as molecular sieves, at a temperature from about 0 to about 50oC. Methanol is the preferred solvent and 25°C is the preferred temperature. It is also preferable that the pH of the reaction mixture be about 4 to about 5.
  • compounds of the formula III may be formed by acylating a compound of the formula IV with a compound having the formula R 3 COCl, and then reducing the resulting amide.
  • the acylation is generally conducted in a polar solvent (e.g., dichloromethane, tetrahydrofuran or ethyl ether), at a temperature from about 0 to about 60°C.
  • the preferred solvent is dichloromethane and the preferred temperature is about 25°C.
  • Examples of reducing agents that may be used to reduce the amide are lithium aluminum hydride and borane dimethyl sulfide.
  • the reduction is typically carried out in a polar solvent (e.g., ether, tetrahydrofuran or DME) at a temperature from about 0°C to about the reflux temperature of the solvent, preferably at about room temperature.
  • the carbobenzoxy group, (CBZ) is then removed by reacting it with ammonium formate in the presence of palladium on charcoal (e.g., 10% palladium on charcoal) to form a compound of formula II.
  • palladium on charcoal e.g., 10% palladium on charcoal
  • a polar solvent such as ethyl acetate or a lower alkanol is used, and the reaction is run at a temperature from about room temperature to about 150°C for about 0.5 to about 24 hours.
  • the reaction is conducted in ethanol at room temperature for about 3 to about 24 hours.
  • the compound of formula II so formed may be converted to a compound of the formula I having the same stereochemistry, as illustrated in scheme 1, by reacting it with a compound of the formula wherein X is
  • reaction is typically carried out in the presence of a base such as triethylamine or potassium t-butoxide, in a polar solvent such as methylene chloride or dichloroethane, and at a temperature from about room temperature to about 150°C.
  • a base such as triethylamine or potassium t-butoxide
  • a polar solvent such as methylene chloride or dichloroethane
  • the reaction is carried out at the reflux temperature in methylene chloride in the presence of triethylamine.
  • novel compounds of the formula I and the pharmaceutically acceptable salts thereof are useful as substance receptor, i.e., they possess the ability to antagonize the effects of substance P at its receptor site in mammals, and therefore they are able to function as therapeutic agents in the treatment of the aforementioned disorders and diseases in an afflicted mammal.
  • the compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the Formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • the compounds of formula I and their pharmaceutically acceptable salts exhibit substance P receptor-binding activity and therefore are of value in the treatment and prevention of a wide variety of clinical conditions the treatment or prevention of which are effected or facilitated by a decrease in substance P mediated neurotransmission.
  • Such conditions include inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or dysthymic disorders, colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina, migraine and Reynaud's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimer's disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis.
  • these compounds are readily adapted to therapeutic use as substance receptor for the control
  • the compounds of the formula I and the pharmaceutically acceptable salts thereof hereafter, referred to as the active compounds of the invention can be administered via either the oral, parenteral or topical routes.
  • these compounds are most desirably administered in dosages ranging from about 5.0 mg up to about 1500 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen.
  • a dosage level that is in the range of about 0.07 mg to about 21 mg per kg of body weight per day is most desirably employed. Variations may nevertheless occur depending upon the species of animal being treated and its individual response to treatment, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • the active compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the three routes previously indicated, and such administration may be carried out in single or multiple doses.
  • the novel therapeutic agents of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • the active compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of an active compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • the aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic.
  • These aqueous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • the activity of the compounds of the present invention as substance receptor is determined by their ability to inhibit the binding of substance P at its receptor sites in bovine caudate tissue, employing radioactive ligands to visualize the tachykinin receptors by means of autoradiography.
  • the substance P antagonizing activity of the herein described compounds may be evaluated by using the standard assay procedure described by M. A. Cascieri et al., as reported in the Journal of Biological Chemistry. Vol. 258, p. 5158 (1983). This method essentially involves determining the concentration of the individual compound required to reduce by 50% the amount of radiolabelled substance P ligands at their receptor sites in said isolated cow tissues, thereby affording characteristic IC 50 values for each compound tested.
  • bovine caudate tissue is removed from a -70°C freezer and homogenized in 50 volumes (w./v.) of an ice-cold 50 mM Tris (i.e., trimethamine which is 2-amino-2-hydroxymethyl-1,3-propanediol) hydrochloride buffer having a pH of 7.7.
  • Tris i.e., trimethamine which is 2-amino-2-hydroxymethyl-1,3-propanediol
  • the homogenate is centrifuged at 30,000 ⁇ G for a period of 20 minutes.
  • the pellet is resuspended in 50 volumes of Tris buffer, rehomogenized and then recentrifuged at 30,000 ⁇ G for another twenty-minute period.
  • the pellet is then resuspended in 40 volumes of ice-cold 50 mM Tris buffer (pH 7.7) containing 2 mM of calcium chloride, 2 mM of magnesium chloride, 40 g/ml of bacitracin, 4 ⁇ g/ml of leupeptin, 2 ⁇ g of chymostatin and 200 g/ml of bovine serum albumin. This step completes the production of the tissue preparation.
  • the radioligand binding procedure is then carried out in the following manner, viz., by initiating the reaction via the addition of 100 ⁇ l of the test compound made up to a concentration of 1 ⁇ M, followed by the addition of 100 ⁇ l of radioactive ligand made up to a final concentration 0.5 mM and then finally by the addition of 800 ⁇ l of the tissue preparation produced as described above.
  • the final volume is thus 1.0 ml, and the reaction mixture is next vortexed and incubated at room temperature (ca. 20°C) for a period of 20 minutes.
  • the tubes are then filtered using a cell harvester, and the glass fiber filters (Whatman GF/B) are washed four times with 50 mM of Tris buffer (pH 7.7), with the filters having previously been presoaked for a period of two hours prior to the filtering procedure. Radioactivity is then determined in a Beta counter at 53% counting efficiency, and the IC 50 values are calculated by using standard statistical methods.
  • the anti-psychotic activity of the compounds of the present invention as neuroleptic agents for the control of various psychotic disorders may be determined primarily by a study of their ability to suppress substance P-induced or substance P agonist induced hypermotility in guinea pigs.
  • This study is carried out by first dosing the guinea pigs with a control compound or with an appropriate test compound of the present invention, then injecting the guinea pigs with substance P or a substance P agonist by intracerebral administration via canula and thereafter measuring their individual locomotor response to said stimulus.
  • lithium diisopropylamide-monotetrahydrofuran 1.5 M in cyclohexanes, 51.9 milliliter, 78 millimole
  • tetrahydrofuran 150 milliliter
  • 3-cyclohexane-1-acetic acid, methyl ester 10 grams, 65 millimole
  • tetrahydrofuran 100 milliliter
  • the resulting solution was diluted with 100 milliliter of one normal hydrochloric acid (HCl) and stirred for one hour.
  • the resulting solution was extracted with ether (3 ⁇ 350 milliliter).
  • the organic phases were combined and washed with water, dried (anhydrous magnesium sulfate (MgSO 4 )) and concentrated in vacuo to afford a residue which on trituration with ether-pentane afforded cis-3-(3-cyclohexenyl)-4-phenyl-1-azetidin-2-ones as oil (21.1 grams, 100%) which was used as such in the next step.
  • reaction mixture was quenched with acetic acid (5M in tetrahydrofuran, 16 milliliter, 80 millimole) in tetrahydrofuran (50 milliliter) and was warmed to room temperature ( ⁇ 25°C). Thereafter it was concentrated under vacuum, diluted with 1 normal HCl and extracted with ether (3 ⁇ 150 milliliter). The combined organic layers were washed with water (2 ⁇ 100 milliliter), dried (anhydrous MgSO 4 ) and filtered. The ether was removed under vacuum to afford orange colored oil (17.5 grams) which was loaded on a flash silica gel column.
  • reaction mixture was filtered through diatomaceous earth (Celite (trademark)) and the filtrate was taken up in aq. ammonium hydroxide.
  • the aqueous phase was extracted with methylene chloride (3 ⁇ 60 milliliter) and dried (anhydrous MgSO 4 ). The solvents were removed under reduced pressure to afford an oily residue (0.56 gram). This was dissolved in ethanol (20 milliliter) and to it 10% palladium on carbon (0.56 gram) and ammonium formate (0.56 gram) were added. The resulting reaction mixture was stirred at 25°C for 4 hours.
  • reaction mixture was filtered through diatomaceous earth (Celite (trademark)) which was washed with ethanol (50 milliliter) and methylene chloride (100 milliliter). The solvents were removed under vacuum to afford solid which was taken up in aqueous ammonium hydroxide and extracted with methylene chloride (3 ⁇ 60 milliliter). The organic extracts were combined and dried (anhydous MgSO 4 ). Evaporation of the solvents under reduced pressure afforded a yellow oil (331 mgs).

Abstract

La présente invention se rapporte à des dérivés aza-bicycliques en pont de la formule (I). Ces nouveaux composés sont utiles dans le traitement de maladies inflammatoires et du système nerveux central ainsi que dans le traitement d'autres affections. L'invention se rapporte également à de nouveaux intermédiaires utilisés dans la synthèse de composés de la formule (I).
PCT/US1993/001429 1992-05-18 1993-02-23 Derives aza-bicycliques en pont utiles comme antagonistes de la substance p WO1993023380A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
DE69331190T DE69331190T2 (de) 1992-05-18 1993-02-23 Überbrückte azabicyclische derivate als substanz p antagonisten
US08/335,726 US5498614A (en) 1992-05-18 1993-02-23 Bridged aza-bicyclic derivatives as substance P antagonist
EP93906038A EP0641328B1 (fr) 1992-05-18 1993-02-23 Derives aza-bicycliques en pont utiles comme antagonistes de la substance p
AT93906038T ATE209186T1 (de) 1992-05-18 1993-02-23 Überbrückte azabicyclische derivate als substanz p antagonisten
DK93906038T DK0641328T3 (da) 1992-05-18 1993-02-23 Broforbundne, azabicykliske derivater som substans P-antagonister

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US88511092A 1992-05-18 1992-05-18
US885,110 1992-05-18

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JP (1) JP2757234B2 (fr)
AT (1) ATE209186T1 (fr)
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DE (1) DE69331190T2 (fr)
DK (1) DK0641328T3 (fr)
ES (1) ES2164657T3 (fr)
FI (2) FI932229A (fr)
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Publication number Priority date Publication date Assignee Title
WO1994016697A1 (fr) 1993-01-19 1994-08-04 Rhone-Poulenc Rorer S.A. Association synergisante ayant un effet antagoniste des recepteurs nk1 et nk2
EP0627221A2 (fr) * 1993-06-04 1994-12-07 Pfizer Inc. Antagonistes de la substance P pour le traitement du vomissement
EP0653208A2 (fr) * 1993-11-17 1995-05-17 Pfizer Inc. Antagonistes de la substance P pour le traitement et la prévention de l'erythème solaire
EP0655246A1 (fr) * 1993-11-30 1995-05-31 Pfizer Inc. Antagonistes de la substance P pour le traitement des maladies causées par Helicobacter Pylori ou d'autres bacteries spirales, ureare-positives, gram-négatives
EP0659409A2 (fr) * 1993-11-23 1995-06-28 Pfizer Inc. Antagonistes de la substance P pour l'inhibition de l'angiogénése
WO1996034857A1 (fr) * 1995-05-02 1996-11-07 Schering Corporation Oximes, hydrazones et olefines substituees, en tant qu'antagonistes des neurokinines
US5688960A (en) * 1995-05-02 1997-11-18 Schering Corporation Substituted oximes, hydrazones and olefins useful as neurokinin antagonists
US5789422A (en) * 1996-10-28 1998-08-04 Schering Corporation Substituted arylalkylamines as neurokinin antagonists
WO2006123182A2 (fr) 2005-05-17 2006-11-23 Merck Sharp & Dohme Limited Sulfones de cyclohexyle pour le traitement du cancer
WO2007011820A2 (fr) 2005-07-15 2007-01-25 Amr Technology, Inc. Tetrahydrobenzazepines substituees par aryle et heteroaryle, et leur utilisation pour bloquer la reabsorption de la noradrenaline, de la dopamine, et de la serotonine
WO2007041052A2 (fr) 2005-09-29 2007-04-12 Merck & Co., Inc. Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
WO2007093827A1 (fr) 2006-02-15 2007-08-23 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Dérivés de trifluoroéthanone substitués par thiophène et thiazole en tant qu'inhibiteurs d'histone désacétylase (hdac)
WO2008120653A1 (fr) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Dérivé d'indoledione
WO2009002495A1 (fr) 2007-06-27 2008-12-31 Merck & Co., Inc. Dérivés de 4-carboxybenzylamino utilisés en tant qu'inhibiteurs de l'histone désacétylase
WO2009111354A2 (fr) 2008-03-03 2009-09-11 Tiger Pharmatech Inhibiteurs de la tyrosine kinase
WO2010114780A1 (fr) 2009-04-01 2010-10-07 Merck Sharp & Dohme Corp. Inhibiteurs de l'activité akt
WO2010132442A1 (fr) 2009-05-12 2010-11-18 Albany Molecular Reserch, Inc. 7-([1,2, 4,]triazolo[1,5,-a]pyridine-6-yl)-4-(3,4-dichlorophényl)-1,2,3,4- tétrahydroisoquinoline et son utilisation
WO2010132487A1 (fr) 2009-05-12 2010-11-18 Bristol-Myers Squibb Company Formes cristallines de (s)-7-([1,2,4]triazolo[1,5-a] pyridin -6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline et leurs utilisations
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WO2013165816A2 (fr) 2012-05-02 2013-11-07 Merck Sharp & Dohme Corp. Compositions de petit acide nucléique interférent (sina)
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WO2014052563A2 (fr) 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Nouveaux composés inhibiteurs de erk
WO2014085216A1 (fr) 2012-11-28 2014-06-05 Merck Sharp & Dohme Corp. Compositions et procédés pour traiter le cancer
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WO2014120748A1 (fr) 2013-01-30 2014-08-07 Merck Sharp & Dohme Corp. Purines 2,6,7,8-substituées utilisées en tant qu'inhibiteurs de hdm2
WO2015034925A1 (fr) 2013-09-03 2015-03-12 Moderna Therapeutics, Inc. Polynucléotides circulaires
US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
US9085531B2 (en) 2004-07-15 2015-07-21 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9156812B2 (en) 2008-06-04 2015-10-13 Bristol-Myers Squibb Company Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
EP3327125A1 (fr) 2010-10-29 2018-05-30 Sirna Therapeutics, Inc. Inhibition au moyen d'interférence arn d'une expression de gène utilisant des acides nucléiques à petit interférent (sina)
WO2019094311A1 (fr) 2017-11-08 2019-05-16 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5
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US11096950B2 (en) 2006-11-01 2021-08-24 Barbara Brooke Jennings Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development
EP4079856A1 (fr) 2010-08-17 2022-10-26 Sirna Therapeutics, Inc. Inhibition médiée par des arn interférents de l'expression génique du virus de l'hépatite b (vhb) à l'aide de petits acides nucléiques interférents (pani)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997018210A1 (fr) * 1995-11-13 1997-05-22 Smithkline Beecham Corporation Composes hemoregulateurs
US7101547B1 (en) 1999-01-22 2006-09-05 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Method for the prevention and treatment of diseases caused by an inflammatory response mediated by endogenous substance P by using anti-substance P antibodies
AU2572800A (en) * 1999-02-18 2000-09-04 Hisamitsu Pharmaceutical Co. Inc. Morphan derivatives or salts thereof and medicinal compositions containing the same
WO2014078568A1 (fr) 2012-11-14 2014-05-22 The Johns Hopkins University Méthodes et compositions pour le traitement de la schizophrénie

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0436334A2 (fr) * 1990-01-04 1991-07-10 Pfizer Inc. Dérivés de 3-Aminopipéridine et N-hétérocycles apparentés
WO1991018899A1 (fr) * 1990-06-01 1991-12-12 Pfizer Inc. Quinuclidines de 3-amino-2-aryle, procede relatif a leur preparation et compositions pharmaceutiques les contenant

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3560510A (en) * 1969-03-05 1971-02-02 Aldrich Chem Co Inc 2-benzhydrylquinuclidines
CA1160229A (fr) * 1979-03-13 1984-01-10 Pieter T. Haken Derives du pyridyliminomethylbenzene
CA1231710A (fr) * 1979-07-19 1988-01-19 Haken Pieter Ten Composes heterocycliques a proprietes fongicides, herbicides et regulatrices de croissance vegetale
EP0100158A3 (fr) * 1982-07-28 1985-03-27 The Upjohn Company Hétéroalkysylalkanoles 3-pyridinyliques, leurs acides alkanoiques et leurs esters
US4552960A (en) * 1983-06-20 1985-11-12 Eli Lilly And Company Fungicidal amines
US4680283A (en) * 1984-09-26 1987-07-14 Merck & Co., Inc. Analogs of substance P and eledoisin
MX18467A (es) * 1988-11-23 1993-07-01 Pfizer Agentes terapeuticos de quinuclidinas
DK0540526T3 (da) * 1990-07-23 1995-04-18 Pfizer Quinuclidinderivater
BR9106905A (pt) * 1990-09-28 1993-08-17 Pfizer Analogos de anel condensado de heterociclos nao aromaticos contendo nitrogenio
US5138060A (en) * 1991-01-03 1992-08-11 Pfizer Inc. Process and intermediates for preparing azabicyclo(2.2.2)octan-3-imines
EP0566589A1 (fr) * 1991-01-10 1993-10-27 Pfizer Inc. Sels de n-alkyle quinuclidinium utilises comme antagonistes de substance p
ES2065175T3 (es) * 1991-03-01 1995-02-01 Pfizer Derivados de 1-azabiciclo(3.2.2)nonan-3-amina.
PL169993B1 (pl) * 1991-03-26 1996-09-30 Pfizer Sposób wytwarzania podstawionych piperydyn PL PL PL PL
HU221634B1 (hu) * 1991-06-20 2002-12-28 Pfizer Inc. Nitrogéntartalmú heterociklusos vegyületek fluor-alkoxi-benzilamino-származékai, eljárás előállításukra és az ezeket tartalmazó gyógyszerkészítmények
TW202432B (fr) * 1991-06-21 1993-03-21 Pfizer

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0436334A2 (fr) * 1990-01-04 1991-07-10 Pfizer Inc. Dérivés de 3-Aminopipéridine et N-hétérocycles apparentés
WO1991018899A1 (fr) * 1990-06-01 1991-12-12 Pfizer Inc. Quinuclidines de 3-amino-2-aryle, procede relatif a leur preparation et compositions pharmaceutiques les contenant

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994016697A1 (fr) 1993-01-19 1994-08-04 Rhone-Poulenc Rorer S.A. Association synergisante ayant un effet antagoniste des recepteurs nk1 et nk2
EP0627221A2 (fr) * 1993-06-04 1994-12-07 Pfizer Inc. Antagonistes de la substance P pour le traitement du vomissement
EP0627221A3 (fr) * 1993-06-04 1995-08-02 Pfizer Antagonistes de la substance P pour le traitement du vomissement.
EP0653208A2 (fr) * 1993-11-17 1995-05-17 Pfizer Inc. Antagonistes de la substance P pour le traitement et la prévention de l'erythème solaire
EP0653208A3 (fr) * 1993-11-17 1995-10-11 Pfizer Antagonistes de la substance P pour le traitement et la prévention de l'erythème solaire.
EP0659409A2 (fr) * 1993-11-23 1995-06-28 Pfizer Inc. Antagonistes de la substance P pour l'inhibition de l'angiogénése
EP0659409A3 (fr) * 1993-11-23 1995-08-09 Pfizer Antagonistes de la substance P pour l'inhibition de l'angiogénése.
EP0655246A1 (fr) * 1993-11-30 1995-05-31 Pfizer Inc. Antagonistes de la substance P pour le traitement des maladies causées par Helicobacter Pylori ou d'autres bacteries spirales, ureare-positives, gram-négatives
WO1996034857A1 (fr) * 1995-05-02 1996-11-07 Schering Corporation Oximes, hydrazones et olefines substituees, en tant qu'antagonistes des neurokinines
US5688960A (en) * 1995-05-02 1997-11-18 Schering Corporation Substituted oximes, hydrazones and olefins useful as neurokinin antagonists
US5696267A (en) * 1995-05-02 1997-12-09 Schering Corporation Substituted oximes, hydrazones and olefins as neurokinin antagonists
US5840725A (en) * 1995-05-02 1998-11-24 Schering Corporation Substituted oximes, hydrazones and olefins as neurokinin antagonists
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US5789422A (en) * 1996-10-28 1998-08-04 Schering Corporation Substituted arylalkylamines as neurokinin antagonists
US9085531B2 (en) 2004-07-15 2015-07-21 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9499531B2 (en) 2004-07-15 2016-11-22 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
WO2006123182A2 (fr) 2005-05-17 2006-11-23 Merck Sharp & Dohme Limited Sulfones de cyclohexyle pour le traitement du cancer
WO2007011820A2 (fr) 2005-07-15 2007-01-25 Amr Technology, Inc. Tetrahydrobenzazepines substituees par aryle et heteroaryle, et leur utilisation pour bloquer la reabsorption de la noradrenaline, de la dopamine, et de la serotonine
US9403776B2 (en) 2005-07-15 2016-08-02 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
WO2007041052A2 (fr) 2005-09-29 2007-04-12 Merck & Co., Inc. Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
WO2007093827A1 (fr) 2006-02-15 2007-08-23 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Dérivés de trifluoroéthanone substitués par thiophène et thiazole en tant qu'inhibiteurs d'histone désacétylase (hdac)
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US11096950B2 (en) 2006-11-01 2021-08-24 Barbara Brooke Jennings Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development
EP2336120A1 (fr) 2007-01-10 2011-06-22 Istituto di ricerche di Biologia Molecolare P. Angeletti S.R.L. Combinaisons contenant indazoles à substitution amide utilisés comme inhibiteurs de la poly(ADP-ribose)polymérase (PARP)
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WO2008120653A1 (fr) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Dérivé d'indoledione
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WO2009002495A1 (fr) 2007-06-27 2008-12-31 Merck & Co., Inc. Dérivés de 4-carboxybenzylamino utilisés en tant qu'inhibiteurs de l'histone désacétylase
WO2009111354A2 (fr) 2008-03-03 2009-09-11 Tiger Pharmatech Inhibiteurs de la tyrosine kinase
US9156812B2 (en) 2008-06-04 2015-10-13 Bristol-Myers Squibb Company Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
US9498476B2 (en) 2008-06-04 2016-11-22 Albany Molecular Research, Inc. Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
WO2010114780A1 (fr) 2009-04-01 2010-10-07 Merck Sharp & Dohme Corp. Inhibiteurs de l'activité akt
US9173879B2 (en) 2009-05-12 2015-11-03 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a ]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
US9604960B2 (en) 2009-05-12 2017-03-28 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
WO2010132442A1 (fr) 2009-05-12 2010-11-18 Albany Molecular Reserch, Inc. 7-([1,2, 4,]triazolo[1,5,-a]pyridine-6-yl)-4-(3,4-dichlorophényl)-1,2,3,4- tétrahydroisoquinoline et son utilisation
WO2010132487A1 (fr) 2009-05-12 2010-11-18 Bristol-Myers Squibb Company Formes cristallines de (s)-7-([1,2,4]triazolo[1,5-a] pyridin -6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline et leurs utilisations
WO2011046771A1 (fr) 2009-10-14 2011-04-21 Schering Corporation Pipéridines substituées qui accroissent l'activité de p53, et utilisations de ces composés
WO2011163330A1 (fr) 2010-06-24 2011-12-29 Merck Sharp & Dohme Corp. Nouveaux composés hétérocycliques utilisés comme inhibiteurs de erk
EP3330377A1 (fr) 2010-08-02 2018-06-06 Sirna Therapeutics, Inc. Inhibition à médiation par interférence arn de caténine (protéine associée à cadhérine), expression du gène bêta 1 (ctnnb1) à l'aide de petit acide nucléique interférent (sian)
WO2012018754A2 (fr) 2010-08-02 2012-02-09 Merck Sharp & Dohme Corp. Inhibition à médiation par interférence arn de caténine (protéine associée à cadhérine), expression du gène bêta 1 (ctnnb1) à l'aide de petit acide nucléique interférent (sian)
EP4079856A1 (fr) 2010-08-17 2022-10-26 Sirna Therapeutics, Inc. Inhibition médiée par des arn interférents de l'expression génique du virus de l'hépatite b (vhb) à l'aide de petits acides nucléiques interférents (pani)
WO2012027236A1 (fr) 2010-08-23 2012-03-01 Schering Corporation Nouveaux dérivés de pyrazolo[1,5-a]pyrimidine utilisés comme inhibiteurs de mtor
WO2012030685A2 (fr) 2010-09-01 2012-03-08 Schering Corporation Dérivés d'indazole utilisables en tant qu'inhibiteurs de la voie erk
WO2012036997A1 (fr) 2010-09-16 2012-03-22 Schering Corporation Dérivés condensés de pyrazole utilisés comme nouveaux inhibiteurs erk
EP3327125A1 (fr) 2010-10-29 2018-05-30 Sirna Therapeutics, Inc. Inhibition au moyen d'interférence arn d'une expression de gène utilisant des acides nucléiques à petit interférent (sina)
EP3766975A1 (fr) 2010-10-29 2021-01-20 Sirna Therapeutics, Inc. Inhibition au moyen d'interférence arn d'une expression de gène utilisant des acides nucléiques à petit interférent (sina)
WO2012087772A1 (fr) 2010-12-21 2012-06-28 Schering Corporation Dérivés d'indazole utiles en tant qu'inhibiteurs de erk
WO2012145471A1 (fr) 2011-04-21 2012-10-26 Merck Sharp & Dohme Corp. Inhibiteurs du récepteur du facteur de croissance 1 analogue à l'insuline
WO2013063214A1 (fr) 2011-10-27 2013-05-02 Merck Sharp & Dohme Corp. Nouveaux composés qui sont des inhibiteurs d'erk
EP3919620A1 (fr) 2012-05-02 2021-12-08 Sirna Therapeutics, Inc. Compositions d'acide nucléique interférent court (sina)
WO2013165816A2 (fr) 2012-05-02 2013-11-07 Merck Sharp & Dohme Corp. Compositions de petit acide nucléique interférent (sina)
WO2014052563A2 (fr) 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Nouveaux composés inhibiteurs de erk
WO2014085216A1 (fr) 2012-11-28 2014-06-05 Merck Sharp & Dohme Corp. Compositions et procédés pour traiter le cancer
WO2014100065A1 (fr) 2012-12-20 2014-06-26 Merck Sharp & Dohme Corp. Imidazopyridines substituées en tant qu'inhibiteurs de hdm2
WO2014120748A1 (fr) 2013-01-30 2014-08-07 Merck Sharp & Dohme Corp. Purines 2,6,7,8-substituées utilisées en tant qu'inhibiteurs de hdm2
WO2015034925A1 (fr) 2013-09-03 2015-03-12 Moderna Therapeutics, Inc. Polynucléotides circulaires
WO2019094311A1 (fr) 2017-11-08 2019-05-16 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5
WO2020033284A1 (fr) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5
WO2020033282A1 (fr) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5

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DE69331190D1 (de) 2002-01-03
FI932229A (fi) 1993-11-19
FI106457B (fi) 2001-02-15
CA2134964A1 (fr) 1993-11-25
EP0641328A1 (fr) 1995-03-08
ATE209186T1 (de) 2001-12-15
PT641328E (pt) 2002-04-29
DK0641328T3 (da) 2002-05-21
US5498614A (en) 1996-03-12
JPH07503483A (ja) 1995-04-13
DE69331190T2 (de) 2002-04-18
JP2757234B2 (ja) 1998-05-25
EP0641328B1 (fr) 2001-11-21
ES2164657T3 (es) 2002-03-01
CA2134964C (fr) 1997-12-30
FI932229A0 (fi) 1993-05-17
FI20000085A (fi) 2000-01-17

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